Lack of effect of short-term DHEA supplementation on the perimenopausal ovary

Circulating levels of dehydroepiandrosterone (DHEA) and its sulfated ester (DHEAS) undergo marked age-associated decline and by the time a woman reaches menopause their levels may be less than half that observed in young adulthood. DHEA supplementation has been shown to improve oocyte quality in women with diminished ovarian function and has beneficial effects in individuals responding poorly in infertility clinics and women over the age of 40. Given that DHEA can serve as a precursor for estrogen synthesis, administration of DHEA to perimenopausal women could potentially counteract the age-associated loss of estrogen from the ovaries and help extend fertility. This randomized controlled study in rhesus macaques aimed to examine the impact of oral DHEA supplementation on reproductive potential, specifically on attenuating loss of key ovarian hormones, during the perimenopause. Similarly to humans, rhesus macaques undergo approximately 28-day menstrual cycles and experience menopause at 24 to 29 years associated with age-related endocrine changes including a decrease in DHEA/S concentrations. Animals were stratified into three 6-animal groups: young adult (mean age, 11.6 years), old control (mean age, 23.1 years), and old DHEA-treated (mean age, 23.5 years). All animals in old control and old DHEA-treated cohorts were considered to be perimenopausal. The old DHEA-treated cohort received 5 mg DHEA supplements every day for 2.5 months. Necropsies were performed when animals were either acyclic or in the early follicular phase of their menstrual cycle. Terminal blood samples were assayed for DHEA sulfate, estradiol, DHT, FSH, testosterone, and AMH. Ovaries were removed and weighed. Hormone levels from each experimental group were expressed as a mean ± standard error of the mean (SEM). Histologic examination revealed an age-associated decrease (P < 0.01) in the mean number of primordial follicles, with the lowest number in the old DHEA-treated cohort. Serum FSH concentrations were higher in the old perimenopausal cohorts compared with the young adults (P < 0.05), and AMH concentrations were lower (P < 0.01). No significant difference was found between the FSH and AMH concentrations of control and DHEA-treated old animals. The old DHEA-cohort showed a marked (P < 0.01) increase in serum DHEAS concentrations at necropsy; however, this was not associated with an increase in estradiol, testosterone, or DHT. Although estrogen levels did not increase with DHEA supplementation, an increase in androgens (testosterone and DHT) was observed, suggesting that exogenous DHEA may be preferentially metabolized via 5-alpha reductase rather than aromatization. The results of this study show that despite 2.5 months of DHEA supplementation, no significant effect on number of primordial follicles or serum concentrations of FSH or AMH were observed. Given circadian variation, one potential limitation of this study is the possibility of significant effects on circulating hormones occurring at times of the day other than morning, when necropsy was performed.